Neurobiology of Aging 83 (2019) 124e129 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Brain reserve, cognitive reserve, compensation, and maintenance: operationalization, validity, and mechanisms of cognitive resilience Yaakov Stern a, Carol A. Barnes b, Cheryl Grady c, Richard N. Jones d, Naftali Raz e,f,* a Cognitive Neuroscience Division, Department of Neurology, Columbia University, New York, NY, USA b Departments of Psychology, Neurology and Neuroscience, and Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ, USA c Rotman Research Institute, Baycrest Centre, and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada d Departments of Neurology and Psychiatry & Human Behavior, Brown University, Providence, RI, USA e Institute of Gerontology and Department of Psychology, Wayne State University, Detroit, MI, USA f Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany article info abstract Article history: Significant individual differences in the trajectories of cognitive aging and in age-related changes of brain Received 25 February 2019 structure and function have been reported in the past half-century. In some individuals, significant Received in revised form 5 March 2019 pathological changes in the brain are observed in conjunction with relatively well-preserved cognitive Accepted 11 March 2019 performance. Multiple constructs have been invoked to explain this paradox of resilience, including brain reserve, cognitive reserve, brain maintenance, and compensation. The aim of this session of the Cognitive Aging Summit III was to examine the overlap and distinctions in definitions and measurement of these Keywords: constructs, to discuss their neural and behavioral correlates and to propose plausible mechanisms of Cognitive aging Measurement individual cognitive resilience in the face of typical age-related neural declines. Ó Animal models 2019 Elsevier Inc. All rights reserved. MRI Functional connectivity 1. Introduction them to withstand the onslaught of cognitive aging and to mitigate the cognitive impairment expected from brain pathology. To Typical aging is accompanied by declines in multiple cognitive explain this finding, scientists have invoked multiple constructs, skills, but trajectories of aging exhibit substantial individual dif- including brain reserve, cognitive reserve, brain maintenance, and ferences. Some individuals show precipitous deterioration, whereas compensation. Brain reserve is a neuroanatomic resource that re- others maintain their cognitive performance to the end of life. flects structural properties of the brain that somehow afford a Although multiple factors may determine individual paths of surplus capacity to maintain cognitive function despite substantial cognitive aging, some people appear more resilient than others to loss of their material substrate. With cognitive reserve, the cogni- the detrimental effects of aging and the associated pathological tive skills and abilities that are acquired before the onset of neural changes. Although its origin remains obscure, the concept of indi- deterioration serve as a hedge againstdor even actively miti- vidual resilience received empirical support in the late 1960s, after gatedloss of function inflicted by the progressive brain failure, scientists observed a discrepancy between the burden of brain while revealing significant individual differences in resilience and pathology and ante-mortem cognitive performance in a series of flexibility. Some people appear to be better than others in main- brain specimens (Blessed et al., 1968). taining structural and functional properties of their brains while These findings, combined with later observations of recovery aging, with multiple factors contributing to variations in success. from brain injury (Satz, 1993) and noninvasive neuroimaging of The mechanisms by which brain and cognitive reserve bolster in- patients with dementia (Stern et al., 1992), have led to the hy- dividual ability to maintain intact cognitive performance over time pothesis that some individuals may possess a reserve that allows and thus contribute to more successful cognitive aging remain a topic for ongoing research. The relationship between brain reserve, cognitive reserve, * Corresponding author at: Institute of Gerontology and Department of Psy- maintenance, and compensation and their contribution to resil- chology, Wayne State University, Detroit, MI 48202, USA, and Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany. Tel.: þ1 ience is the focus of a lively debate within the research community. 313 577 2297; fax: þ1 313 664 666. The arguments center on the core issues of definition and E-mail address: [email protected] (N. Raz). 0197-4580/$ e see front matter Ó 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.neurobiolaging.2019.03.022 Y. Stern et al. / Neurobiology of Aging 83 (2019) 124e129 125 measurement of each construct, their differential validity, and their that, in individuals with comparable clinical severity of mild neural mechanisms, as well as their potential for guiding devel- cognitive impairment or Alzheimer’s disease, those with higher opment of interventions to mitigate the effects of cognitive aging on levels of these cognitive reserve proxies have more advanced Alz- behavior. Regardless of how the related and partially overlapping heimer’s type pathology (Bennett et al., 2003; Ewers et al., 2013; constructs are understood in the overarching notion of resilience, Stern et al., 1992). These observations indicate that individuals they are all theoretical entities that currently cannot be measured with higher cognitive reserve can better cope with the brain directly. Therefore, a problem of measuring resilience and evalu- changes and can maintain higher function despite brain ating the validity of its indicators needs to be addressed. deterioration. During this session of the Cognitive Aging Summit III, chaired by Cognitive reserve is typically measured via proxies that sum- Naftali Raz, the speakers sought to define and describe these con- marize experiences that affect reserve, such as educational and structs to explain the phenomenon of resilience: brain reserve, occupational attainment (Stern et al., 1999). Although these mea- cognitive reserve, maintenance, and compensation. They examined sures moderate the relationship between brain changes and clinical the fundamental definition and measurement issues facing the status, they are not direct measures of cognitive reserve and do not study of resilience and discussed models and mechanisms that reflect the underlying brain processes through which cognitive describe brain adaptation to age-related changes, and, in principle, reserve operates. Many investigators have studied the “neural could guide interventions to alleviate age-related cognitive implementation” of cognitive reserve. As these relationships declines. become better understood, proxies for cognitive reserve may be replaced with direct measures of specific brain processes that un- 2. Reserve: an evolving concept derlie cognitive reserve. For example, our group has recently described a pattern of brain activation that occurs when people are 2.1. Yaakov Stern performing almost any task and that is expressed to a greater de- gree by people with higher IQ than those with lower IQ (Deary et al., The term reserve describes the difference between the degree of 2004). Furthermore, expression of this pattern moderates the brain damage observed in an individual and the clinical manifes- relationship between age-related brain changes and performance. tation of that damage. At least 2 models explain reserve. Another group has described a resting brain oxygenation level The brain reserve model defines reserve as a physical trait: some dependent pattern that seems to be associated with increased people have larger brains, with more neurons and synapses, which cognitive reserve (Franzmeier et al., 2017). Expression of such a may allow their brains to absorb more injury before cognitive pattern may be a more direct measure of cognitive reserve, and function is affected (Katzman et al., 1988; Satz, 1993). Brain reserve examination of the pattern may yield information about how may therefore be thought of as individual differences in the hard- cognitive reserve is neurally implemented. ware of the brain. Brain reserve can be conceived as a passive entity, Brain reserve and cognitive reserve are not mutually exclusive. which reflects an overt expression of impairment only after an in- Structural features and dynamic network capacity both play a role dividual’s capacity falls below a crucial threshold of loss of the brain in how the brain functions in the face of age-related brain changes substrate (Satz, 1993). People with greater initial brain capacity can and pathology. Furthermore, the concept of brain maintenance therefore tolerate more neurological attrition in absolute terms suggests that life experiences can mitigate age-related brain before crossing into impairment. However, some people can changes. A better understanding of the brain’s adaptability will maintain their brain better than others throughout the aging pro- enable approaches to preserve or increase both brain and cognitive cess as a function of genetics and life experienceda concept called reserve to delay or reverse the effects of age-related cognitive